The ank gene story

Abstract

Available online http://arthritis-research.com/content/3/2/077 Introduction A landmark investigation into the genetic basis of murine progressive ankylosis has clarified the physiologic role of extracellular inorganic pyrophosphate (ePPi) in suppressing pathologic deposition of basic calcium phosphate (BCP) (an inclusive term for hydroxyapatite, octacalcium phosphate, and tricalcium phosphate) in articular tissue [1]. A cell membrane protein, ANK, affects ePPi concentrations and the balance of mineralization in articular tissues. Excess ePPi promotes pathologic mineralization with CPPD crystalsExcess accumulation of ePPi has long been recognized as an important factor in the mineralization of cartilage with calcium pyrophosphate dihydrate (CPPD) crystals. Elevated levels of ePPi are routinely noted in synovial fluids of patients with CPPD deposition disease [2,3]. Chondrocytes are the likely source of the ePPi that participates in the formation of these crystals [4,5]. The elaboration of ePPi by chondrocytes is a bioregulable process, enhanced by transforming growth factor β, ascorbate, retinoic acid, bone morphogenetic protein, transglutaminase, and thyroid hormones and diminished by parathyroid-hormone-related peptide isoforms, insulin-like growth factor-1, tumor necrosis factor α, and interleukin 1. Porcine chondrocytes from aged donors make more ePPi than do chondrocytes from young donors [6]. Signaling mechanisms involved in the regulation of ePPi formation are poorly understood, but adenylyl cyclase activation decreases and protein kinase C activation increases the accumulation of ePPi in media surrounding cartilage or chondrocyte cultures [7]. In addition to causing CPPD crystal formation, excess ePPi accumulation may also affect BCP mineralization.CPPD crystal deposits and elevated ePPi levels are particularly prominent in adult hypophosphatasia, congenital deficiency of tissue-nonspecific alkaline phosphatase. In hypophosphatasia, the predominant phenotypic disease expressions are rickets and osteomalacia. Murine models of hypophosphatasia indicate that the nucleation and initial growth of BCP crystals within matrix vesicles of mineralizing CommentaryThe ank gene story AbstractThe underlying molecular defect resulting in the abnormal calcification observed in ank/ank mice has been identified. The responsible nonsense mutation affects the protein product of ank, resulting in diminished production of extracellular inorganic pyrophosphate, an important inhibitor of nucleation and of the growth of apatite crystals. The ank gene product is one of several cell membrane proteins, including ectonucleoside triphosphate pyrophosphohydrolase enzymes and alkaline phosphatase, that regulate extracellular inorganic pyrophosphate levels and thereby regulate mineralization.

Development of synovial joints

“…Another similar mouse mutant is tiptoe walking, which arises due to a mutation in a membrane-bound ectoenzyme that produces extracellular PPi from nucleoside triphosphates (Okawa et al, 1998). In fact, it appears that a fine balance of PPi is needed to maintain normal articular morphology, and to function with either an excess or a deficiency, resulting in the deposition of CPPD or hydroxyapaptite crystals, respectively, which occurs in over 40% of the elderly (reviewed by Ryan, 2001).…”

Renal calcium stones: insights from the control of bone mineralization

“…More recently, expression of ANK in Xenopus oocytes has confirmed 32 PP i influx into the oocytes, which showed saturation by external PP i with an apparent K m of ∼2 μ m (Gurley et al 2006 b ). The ANK protein is therefore unlikely to be an anion channel, but little else is known about ANK function (whether facilitated transporter, symporter or antiporter) and its specificity with respect to anions such as phosphate or even ATP (suggested by Ryan, 2001).…”

Akt1 in murine chondrocytes controls cartilage calcification during endochondral ossification under physiologic and pathologic conditions

“…Extracellular PPi accumulation is regulated by a transmembrane protein progressive ankylosis (ANK) for extracellular channeling, nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) for generation from nucleoside triphosphates, and tissue‐nonspecific alkaline phosphatase (TNAP) for hydrolyzation (4–6).…”